Mortality related to the epidemic of prescription drug misuse exceeds that due to motor vehicle crashes. Driven by trends in prescription opioid medication use and availability, the public health response to this problem is in early stages and involves deployment of several emerging evidence-based approaches, including distribution of naloxone, an opioid antagonist antidote, to high-risk individuals. In Rhode Island (RI), an innovative and unique program involves pharmacist-initiated prescription and distribution of naloxone. Neighboring Massachusetts (MA) has advanced a similar pharmacy-based naloxone (PBN) program, employing a standing order model. Two retail pharmacy chains, CVS and Walgreens, are taking part in the state programs. As the country expands the implementation of naloxone through the medical system, refining models for PBN as well as identifying barriers and facilitators to PBN uptake will be key. We propose a demonstration project to systematically expand, evaluate the implementation of, and document PBN provision in CVS Pharmacies in two New England states. We developed and successfully implemented an online continuing pharmacy education course and created protocols for pharmacies to supply, order, and provide naloxone to patients. By expanding PBN across all 418 RI and MA CVS pharmacies (of varying size, types/hours, location, population served), we can identify important organizational and community factors associated with successful implementation that can be generalized to pharmacy chains and communities nationwide. The overarching goal of this study is to promote the safe use of opioid analgesic medications, and reduce negative consequences of their misuse, through pharmacy-based innovations. Specific aims are to: Aim 1: Implement PBN in all RI (n=63) and MA (n=355) CVS pharmacies. Aim 2: Determine organizational factors associated with successful implementation of PBN. 2.a. Quantify the success of PBN implementation by measuring pharmacist compliance with indication for naloxone and counseling on naloxone through secret shopper and crowdsourcing-generated evaluations; and 2.b. conduct surveys of pharmacists to identify organizational factors associated with successful implementation of PBN. Aim 3: Evaluate the impact of implementing PBN by measuring change in proximal [a) naloxone dispensed; b) pharmacist PDMP use]; and distal outcomes [c) use of naloxone in an overdose by laypersons prior to emergency medical system arrival; d) increased substance use disorder treatment uptake; and e) reach: proportion of patients at risk who receive PBN] over time, comparing within and between the two states. Aim 4: Assess project sustainability and disseminate project results, in collaboration with AHRQ, to policymakers and those responsible for quality improvement and patient safety in pharmacy and community settings. This project leverages an unprecedented collaboration between private and research entities at a critical point in the prescription opioid epidemic, in two states well- poisd to incubate PBN and prepare models and recommendations for nationwide scale-up.